Mitochondria and immunity in chronic fatigue syndrome
Introduction
The biological underpinnings of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) are still the subject of considerable research. ME/CFS is generally accepted to be a heterogenous condition, characterized by chronic unexplained fatigue, post-exertional malaise and an array of multi-system symptomatology. A number of different criteria and ME/CFS sub-types have been proposed, which confounds comparisons between studies (Fukuda et al., 1994; Carruthers et al., 2011; Maes et al., 2013a; Sharpe et al., 1991), including as to the relevant pathophysiological changes and therefore treatment targets. Confusion, and perhaps tribalism, regarding classification criteria considerably contribute to the non-replication of data in ME/CFS studies, including as to prevalence rates (Maes et al., 2013a). This conceptual disarray contributes to the relatively low research funding allocated to research on ME/CFS (Dimmock et al., 2016) (Fig. 1).
As well as the wide variety of pathophysiological processes that can occur in ME/CFS (Missailidis et al., 2019), there is also considerable heterogeneity as to etiology, with ME/CFS being triggered by infection or other body stresses/traumas in some ME/CFS patients, but not in others (Chu et al., 2019). This heterogeneity is further confounded by the array of ‘comorbidities’ that are commonly evident in people classed with ME/CFS, including: fibromyalgia, depression, migraine, anxiety, irritable bowel syndrome, cognitive impairment, sensory sensitivity, autonomic dysregulation and postural orthostatic tachycardia (Chu et al., 2019). ME/CFS has high comorbidity levels: 75% with major depressive disorder (MDD), 40–70% with fibromyalgia and 15–20% with IBS (Dansie et al., 2012). All of these conditions are associated with alterations in mitochondrial function (Favero et al., 2019; Anderson, 2018; Slyepchenko et al., 2016), immune activity (Burns et al., 2019; Andrés-Rodríguez et al., 2019; Anderson et al., 2014), intestinal dysregulation (Clos-Garcia et al., 2019; Anderson and Maes, 2020a) and circadian dysregulation (Caumo et al., 2019; Codoñer-Franch and Gombert, 2018), as well as with co-ordinated changes in such factors across these conditions (Anderson and Maes, 2017a; Martin-Subero et al., 2016).
ME/CFS is more commonly diagnosed in women, as are many of its comorbidities, with an average age of onset of 33 years. The classification and pathophysiology of ME/CFS ‘comorbidities’, such as migraine, depression and fibromyalgia, have met with similar conceptual criticisms to that of ME/CFS (Anderson, 2018).
With these limitations in mind, the present article reviews the pathophysiology of ME/CFS, leading to a more integrative model of this complex presentation, with future research and treatment implications.
Section snippets
Gut microbiome, immunoglobulin-A and vitamin A
Butyrate also promotes t-cell-independent immunoglobulin (Ig)A class switching recombination (CSR), with butyrate levels in human stools positively correlating with IgA levels (Isobe et al., 2020). This is mediated by the immune-regulatory effects of butyrate-induced transforming growth factor (TGF)-β1 and all-trans retinoic acid (ATRA), leading to the production by CD103 + CD11b + dendritic cells. Both TGF-β1 and ATRA are critical for t-cell-independent IgA CSR, with butyrate-induced IgA
Future research directions
Does stress-associated re-awakening of dormant viruses lead to alterations in 14–3-3 isoforms (Riedl et al., 2019; Gupta et al., 2018), thereby impacting on the mitochondrial melatonergic pathway in immune cells?
The role of the opioidergic system in the regulation of viruses, including on virus re-awakening and its consequences for the immune response, will be important to determine, including as to how this is modulated by pineal melatonin.
Does gut dysbiosis, via the suppression of butyrate's
Opioidergic
Low-dose naltrexone can have utility in ME/CFS (Bolton et al., 2020), as well as in the treatment of its common comorbidities, viz. fibromyalgia (Cote et al., 2018) and MDD (Mischoulon et al., 2017), suggesting practical clinical application. Although politically sensitive due to the ‘opioid epidemic’, it will be important to determine the role of different opioid ligands and receptors in ME/CFS. The efficacy of low-dose naltrexone may be mediated by the compensatory increase in β-endorphin,
Ketone diet
Although single case reports have indicated some utility of a ketogenic diet in ME/CFS, there are no experimentally controlled studies of the clinical efficacy of the ketogenic diet in ME/CFS patients. The ketogenic diet modulates mitochondrial metabolism and can increase orexin (Valenzano et al., 2019). β-hydroxybutyrate is the main mediator of the ketogenic diet and positively modulates mitochondrial function in skeletal muscle by decreasing ceramide production (Parker et al., 2018). The
Sodium butyrate
As noted throughout, many of the effects of gut dysbiosis in ME/CFS may be mediated by a decrease in butyrate. This is due to butyrate's effects, including via HDAC inhibition, on mitochondria and melatonin, and thereby on glia and immune cell function. It is also of note that butyrate epigenetically regulates the mitochondria of skeletal muscle in rodents (Hong et al., 2016).
Melatonin
Melatonin improves fatigue, concentration and activity levels in people with ME/CFS, especially in those with indicants of suboptimal pineal gland activity (van Heukelom et al., 2006). As noted above, melatonin, via Bmal1, is a major regulator of mitochondrial and immune function. Melatonin also decreases levels of the κ-opioid receptor, which may be relevant to the management of ME/CFS, including via the inhibition of the heightened sympathetic nervous system activity that is evident.
Vagal nerve stimulation and isometric yoga
Sitting isometric yoga is beneficial in ME/CFS, at least in part via an increase in vagal nerve activity that acts to redress the imbalance in the autonomic nervous system in ME/CFS (Oka et al., 2018). More direct stimulation of the vagal nerve may have utility in ME/CFS, with effects that are at least partially determined by enteric glia cells, which are significant regulators of the vagal nerve's dampening of gut inflammation (Langness et al., 2017).
Probiotics
A recent pilot study of the use of probiotics in 9 ME/CFS patients showed a significant modulation of indices of intestinal and systemic inflammation, coupled to an improvement in fatigue and mood (Venturini et al., 2019). Two previous small sample studies also indicate probiotic efficacy in the treatment of ME/CFS, showing improvements in anxiety and a reduction in immune-inflammatory markers (Roman et al., 2018). A larger number of studies have looked at the efficacy of probiotics in the
Vitamin A
The effects of vitamin A on mitochondrial and immune function would suggest that it should be monitored in ME/CFS patients and supplemented when deficient.
Nutriceuticals
Herba Epimedii is a traditional Chinese Medicine, which has been shown to have some efficacy in the treatment of ME/CFS (Chi et al., 2017). These authors have investigated a number of possible alternative treatments for ME/CFS, highlighting some common benefits via the upregulation of the TCA cycle (Chi et al., 2016).
CoEnzyme Q10
Coenzyme Q10 is another common supplement that can improve mitochondrial function and has some proven, if limited, utility in ME/CFS (Maes et al., 2009).
Conclusion
The poor conceptualization of ME/CFS as a medical condition(s) has clearly contributed to its relative under-funding for research on its biological underpinnings. In some ways, this may actually be reflective of the complexity of the condition(s), suggesting that insight to its biological underpinnings is likely to considerably improve the conceptualization and treatment of similarly complex presentations, including fibromyalgia, MDD, dementia and migraine. Two hubs may be of particular
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Conflicts of interest
The authors declare no conflict of interest.
Acknowledgement
Not applicable.
References (266)
- et al.
A Neutrophil Timer Coordinates Immune Defense and Vascular Protection
Immunity
(2019) - et al.
MiR-155-5p controls colon cancer cell migration via post-transcriptional regulation of Human Antigen R (HuR)
Cancer Lett.
(2018) - et al.
Epigenetic components of myalgic encephalomyelitis/chronic fatigue syndrome uncover potential transposable element activation
Clin. Ther.
(2019) Neuronal-immune interactions in mediating stress effects in the etiology and course of schizophrenia: role of the amygdala in developmental co-ordination
Med. Hypotheses
(2011)Linking the biological underpinnings of depression: role of mitochondria interactions with melatonin, inflammation, sirtuins, tryptophan catabolites, DNA repair and oxidative and nitrosative stress, with consequences for classification and cognition
Prog. Neuro-Psychopharmacol. Biol. Psychiatry
(2018)- et al.
Up-regulation of the human- specific CHRFAM7A gene in inflammatory bowel disease
BBA. Clin.
(2016) - et al.
Enteric glial-mediated enhancement of intestinal barrier integrity is compromised by morphine
J. Surg. Res.
(2017) - et al.
Regulation of miR- 155 biogenesis in cystic fibrosis lung epithelial cells: antagonistic role of two mRNA- destabilizing proteins, KSRP and TTP
Biochem. Biophys. Res. Commun.
(2013) - et al.
Chronic fatigue syndrome and circulating cytokines: a systematic review
Brain Behav. Immun.
(2015) - et al.
A formal analysis of cytokine networks in chronic fatigue syndrome
Brain Behav. Immun.
(2010)
A formal analysis of cytokine networks in chronic fatigue syndrome
Brain Behav. Immun.
The RNA binding protein tristetraprolin influences the activation state of murine dendritic cells
Mol. Immunol.
Comorbidity in chronic fatigue syndrome/myalgic encephalomyelitis: a nationwide population-based cohort study
Psychosomatics.
Shared microglial mechanisms underpinning depression and chronic fatigue syndrome and their comorbidities
Behav. Brain Res.
Metabolic mechanism of a polysaccharide from Schisandra chinensis to relieve chronic fatigue syndrome
Int. J. Biol. Macromol.
Characterization of a protein-bound polysaccharide from Herba Epimedii and its metabolic mechanism in chronic fatigue syndrome
J. Ethnopharmacol.
Gut microbiome and serum metabolome analyses identify molecular biomarkers and altered glutamate metabolism in fibromyalgia
EBioMedicine.
Mitoprotective dietary approaches for myalgic encephalomyelitis/chronic fatigue syndrome: caloric restriction, fasting, and ketogenic diets
Med. Hypotheses
Conditions comorbid with chronic fatigue in a population-based sample
Psychosomatics.
Activation of nicotinic acetylcholine α7 receptor attenuates progression of monocrotaline-induced pulmonary hypertension in rats by downregulating the NLRP3 inflammasome
Front. Pharmacol.
δ-Opioid receptors: pivotal role in intermittent hypoxia-augmentation of cardiac parasympathetic control and plasticity
Auton. Neurosci.
Melatonin reduces membrane rigidity and oxidative damage in the brain of SAMP8 mice
Neurobiol. Aging
Myalgia and chronic fatigue syndrome following immunization: macrophagic myofasciitis and animal studies support linkage to aluminum adjuvant persistency and diffusion in the immune system
Autoimmun. Rev.
Melatonin inhibits proliferation and invasion via repression of miRNA-155 in glioma cells
Biomed. Pharmacother.
Control of oxidative phosphorylation by vitamin A illuminates a fundamental role in mitochondrial energy homoeostasis
FASEB J.
Microglial IRF5-IRF4 regulatory axis regulates neuroinflammation after cerebral ischemia and impacts stroke outcomes
Proc. Natl. Acad. Sci. U. S. A.
Viruses as modulators of mitochondrial functions
Adv. Virol.
Pathoetiology and pathophysiology of borderline personality: role of prenatal factors, gut microbiome, mu- and kappa-opioid receptors in amygdala-PFC interactions
Prog. Neuro-Psychopharmacol. Biol. Psychiatry
Endometriosis pathoetiology and pathophysiology: roles of vitamin A, estrogen, immunity, adipocytes, gut microbiome and melatonergic pathway on mitochondria regulation
Biomol. Concepts.
Integrating pathophysiology in migraine: role of the gut microbiome and melatonin
Curr. Pharm. Des.
Gut Dysbiosis Dysregulates Central and Systemic Homeostasis via Decreased Melatonin and Suboptimal Mitochondria Functioning: Pathoetiological and Pathophysiological Implications
Melatonin. Res.
Daytime orexin and night-time melatonin regulation of mitochondria melatonin:roles in circadian oscillations systemically and centrally in breast cancer symptomatology
Melatonin. Res.
Autism spectrum disorders: role of pre- and post- natal GammaDelta (γδ) T Cells and immune regulation
Curr. Pharm. Des.
Local melatonin regulates inflammation resolution: a common factor in neurodegenerative, psychiatric and systemic inflammatory disorders
CNS Neurol. Disord. Drug Targets
How Immune-inflammatory Processes Link CNS and Psychiatric Disorders: Classification and Treatment Implications
CNS Neurol. Disord. Drug Targets
Interactions of tryptophan and its catabolites with melatonin and the alpha 7 nicotinic receptor in central nervous system and psychiatric disorders: role of the aryl hydrocarbon receptor and direct mitochondria regulation
Int. J. Tryptophan. Res.
Gut dysbiosis dysregulates central and systemic homeostasis via suboptimal mitochondrial function: assessment, treatment and classification implications
Curr. Top. Med. Chem.
Role of opioidergic system in regulating depression pathophysiology
Curr. Pharm. Des.
Biological phenotypes underpin the physio-somatic symptoms of somatization, depression, and chronic fatigue syndrome
Acta Psychiatr. Scand.
Gut permeability and microbiota in parkinson's disease: role of depression, tryptophan catabolites, oxidative and nitrosative stress and melatonergic pathways
Curr. Pharm. Des.
Multiple Sclerosis: Melatonin, Orexin, and Ceramide Interact with Platelet Activation Coagulation Factors and Gut-Microbiome- Derived Butyrate in the Circadian Dysregulation of Mitochondria in Glia and Immune Cells
Int. J. Mol. Sci.
Machine learning to understand the immune-inflammatory pathways in fibromyalgia
Int. J. Mol. Sci.
Metabolic profiling reveals anomalous energy metabolism and oxidative stress pathways in chronic fatigue syndrome patients
Metabolomics.
miR-155 Drives Metabolic Reprogramming of ER+ Breast Cancer Cells Following Long-Term Estrogen Deprivation and Predicts Clinical Response to Aromatase Inhibitors
Cancer Res.
Comorbidities treated in primary care in children with chronic fatigue syndrome / myalgic encephalomyelitis: A nationwide registry linkage study from Norway
BMC Fam. Pract.
Alcohol-induced miR-155 and HDAC11 inhibit negative regulators of the TLR4 pathway and lead to increased LPS responsiveness of Kupffer cells in alcoholic liver disease
J. Leukoc. Biol.
Interleukin-1-related activity and hypocretin-1 in cerebrospinal fluid contribute to fatigue in primary Sjögren's syndrome
J. Neuroinflammation
Vagotonic effects of enkephalin are not mediated by sympatholytic mechanisms
Exp. Biol. Med. (Maywood)
Mitochondrial abnormalities in the postviral fatigue syndrome
Acta Neuropathol.
Interaction of melatonin and Bmal1 in the regulation of PI3K/AKT pathway components and cellular survival
Sci. Rep.
Cited by (41)
Health system support among patients with ME/CFS in Switzerland
2023, Journal of Taibah University Medical SciencesAnalysis of post COVID-19 condition and its overlap with myalgic encephalomyelitis/chronic fatigue syndrome
2022, Journal of Advanced ResearchCitation Excerpt :In both COVID-19 and ME/CFS patients, serious tissue and organ damage was associated with increased reactive oxygen species (ROS) formation, which follows the disbalanced cytokine production [132,133]. Pro-inflammatory cytokines, dysregulated T-cell signalling, abnormal mitochondrial OXPHOS, and elevated level of ROS (oxidative stress) may facilitate development of ME/CFS [134,135]. High serum TNFα content in patients with ME/CFS was shown to downregulate mitochondrial and cellular bioenergetics [94,136].